Neurodegeneration is a hallmark of aging. Projection studies indicate that the increase in life expectancy will have a significant impact in the number of cases of different types of neurodegenerative conditions and become a serious public health concern. One of the main gaps in neurodegeneration is the identification of early molecular changes that lead to deterioration of the nervous systems in the context of aging and toxic environmental factors. Normal brain function depends on the efficient integration of different cell types that compose the neurovascular unit and work together to maintain homeostasis of the central nervous system. Inflammation plays an important role in tissue repair and regeneration. Conversely, deregulated inflammation can elicit different types of pathological conditions. Neuroinflammation and disruption of the neurovascular unit play a critical role on the development of several neurodegenerative conditions such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis and other types of dementia. The primary goal of this supplement proposal is to determine if endothelial c-Myc plays a role in brain homeostasis during aging and neurotoxic stress leading to neurodegeneration. Unpublished findings from our parent R01 suggest that endothelial c-Myc expression regulates neuroinflammation and neurodegeneration- associated pathways in the brain. This proposal will consist of additional studies associated with Aim 2 of the parent award, to determine if our animal model shows signs of behavioral and pathological changes commonly described in neurodegeneration. We propose to test the hypothesis that endothelial c-Myc is essential to maintain the neurovascular unit function and contribute to protection against neurodegenerative diseases. In Aim 1, we will characterize the brain phenotype of endothelial c-Myc knockout mice throughout aging in the context of neurodegeneration. In Aim 2, we will determine the relevance of endothelial c-Myc for neuroprotection. Our findings will have a significant impact by identifying a novel potential mechanism involved in neurodegeneration.